Q:Do evidence-based data support combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB)? A:The availability of 2 distinct classes of drugs that effectively suppress the renin-angiotensin-aldosterone system inevitably leads to the question of whether a combination of these agents provides benefits beyond those observed with monotherapy. Although some small studies have demonstrated the effectiveness of an ACE inhibitor and an ARB in combination, no large prospective trials have compared these drug classes with each other or evaluated them when used together. Recommendations for study design. Study results have been difficult to assess because there is no objective definition of additive effects. A properly conducted study should ascertain the optimal dose response of drug A before drug B is added to the regimen. For example, if blood pressure response is being used as the surrogate marker of effectiveness of an ACE inhibitor or ARB, the dosage of drug A would be titrated to the maximum tolerated dosage or the dosage at which no further reduction in blood pressure was observed. At this point, drug B would be added and titrated appropriately to determine the maximum combined effect of the 2 agents. Other surrogate markers can be used in evaluating ACE inhibitors and ARBs. For example, in patients with either diabetic or nondiabetic progressive renal disease, the rate of decline in glomerular filtration rate or quantitative proteinuria can be used as a surrogate marker of effectiveness. In patients with congestive heart failure (CHF), improvement in treadmill exercise time and reduction in frequency of hospitalizations for CHF have been used as surrogate markers of effectiveness. In clinical practice, few medications are prescribed at optimum or maximum manufacturer’s recommended dosages. Many physicians hesitate to uptitrate medications, even within their recommended dosage ranges and in the absence of adverse effects. ACE inhibitors and ARBs are usually prescribed at low to moderate dosages. In patients with CHF, low blood pressure may limit optimum dosing of these agents. In patients with renal disease and significant azotemia, up-titration may also be limited by excessive rises in serum creatinine concentration associated with drug-induced decreases in glomerular filtration rate. In the presence of these comorbidities, clinicians are understandably reluctant to up-titrate drug dosages. These factors limit the achievement of maximum dose responses with both classes of agents. Inconclusive evidence. Two recent studies illustrate the difficulty of determining whether truly additive effects of ACE inhibitors and ARBs are seen on selected surrogate disease markers. One study sought to determine the effects of combination therapy on proteinuria in normotensive patients with IgA nephropathy. 1 Eight patients were successively given an ACE inhibitor alone, the ARB losartan(Drug information on losartan) alone, combination therapy, and single-agent therapy at a doubled dosage. Both the ACE inhibitor and losartan significantly reduced proteinuria; doubled dosages did not reduce it further. Combination therapy reduced proteinuria to a much greater degree than either agent alone. The authors hypothesized that combination therapy had an additive, dosedependent antiproteinuric effect, independent of the drug-related reduction in blood pressure. However, they could not definitively conclude that the antiproteinuric effect of combination therapy was unrelated to reduction in blood pressure. The maximum doses of ACE inhibitors used in this study were well below the maximum recommended dosages for the treatment of hypertension and may not represent optimum dosages. It is unclear whether, if the maximum effective dose responses had been attained, the apparent additive effect of combination therapy would have been the same. The second study included more than 5000 patients with CHF who were given the ARB valsartan(Drug information on valsartan) in addition to the standard therapeutic regimen.2 Ninety- three percent of the participants were taking an ACE inhibitor when valsartan was added. After 27 months of follow-up, there was a 13% reduction in combined all-cause mortality and morbidity and a 27.5% reduction in heart failure hospitalizations in the valsartan group. The authors concluded that valsartan had an additive effect when combined with standard therapy. However, there was no protocol control over the dosage or dose titration of ACE inhibitors used in the study, and many patients with CHF cannot tolerate higher doses of ACE inhibitors. Therefore, it is risky to assume that the results were attributable to combination therapy. A final caveat. My purpose here is to encourage a critical review of clinical studies. Be wary of study designs and results that do not appear to support the author’s conclusions. Current evidence suggests that there may be significant advantages to combination therapy with ACE inhibitors and ARBs. However, before we can make a definitive assessment, we need clinical trials that are properly designed to ensure appropriate titration to maximum tolerated or effective dosages, as well as to determine the potential magnitude of benefit and delineate safety concerns.